Novel alpha6 preferring GABA-A receptor ligands based on loreclezole

The family of GABA-A receptors contains nineteen mammalian subunits from which pentameric, GABA gated anion channels are assembled. The subunit encoded by the GABRA6 gene is highly expressed in the cerebellum and the receptors to which it contributes have recently been demonstrated to be a promising candidate as a novel drug target. Here we examined a series of loreclezole derivatives for potentially selective action at α6β3γ2 receptors with the help of computational methods and functional testing with the two-electrode voltage clamp technique. The synthetic routes to some previously published ligands were improved, and a new derivative was synthesized based on computational docking results. This new loreclezole derivative, [3-(2-chloro-4-methylphenyl)-3-methylbutanenitrile (40)], was shown to display stronger modulatory action in concatenated α6β3γ2 receptors compared to their α1β3γ2 counterpart. The hypothetical bound state structure provides valuable guidance for future design of selective therapeutics.